10-110644496-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001134363.3(RBM20):c.42C>G(p.Ser14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000046 in 1,523,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.874

Genes affected

RBM20 (HGNC:27424): (RNA binding motif protein 20) This gene encodes a protein that binds RNA and regulates splicing. Mutations in this gene have been associated with familial dilated cardiomyopathy. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06262857).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.42C>G	p.Ser14Arg	missense_variant	1/14	ENST00000369519.4
RBM20	XM_017016103.3	c.26+1056C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.42C>G	p.Ser14Arg	missense_variant	1/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000852 AC: 1 AN: 117436 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64800

Gnomad AFR exome AF: 0.000330

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1370980 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 676228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74436

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000302

ExAC AF: 0.0000422 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2012

p.Ser14Arg (AGC>AGG): c.42 C>G in exon 1 of the RBM20 gene (NM_001134363.1). The Ser14Arg variant in the RBM20 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser14Arg results in a semi-conservative amino acid substitution of a neutral, polar Serine with a positively charged Arginine at a position that is conserved across species. In silico analysis predicts Ser14Arg is probably damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Ser14Arg was not observed in approximately 2,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with cardiomyopathy. With the clinical and molecular information available at this time, we cannot definitively determine if Ser14Arg is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2022

The p.S14R variant (also known as c.42C>G), located in coding exon 1 of the RBM20 gene, results from a C to G substitution at nucleotide position 42. The serine at codon 14 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.46	N
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	0.98	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Vest4		0.18
MutPred		0.17		Loss of glycosylation at S14 (P = 0.002);
MVP		0.54
ClinPred		0.36	T
GERP RS		3.3
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs541043583; hg19: chr10-112404254;